Proliferation is known to be active generally in cancerous cells compared with normal cells, and in many cases, it is thought that the disorderliness of proliferation due to an abnormality in the cell cycle control mechanism is the cause of cancer. A mitotic phase (M phase) of the cell cycle is the step of equally partitioning a chromosome into daughter cells, and a strict control in the process is essential for cell proliferation and survival. Therefore, it is believed that the inhibition of M phase progression is an effective means for inhibiting cell proliferation, and practically, antitumor agents targeting M phase such as taxol, vincristine, or the like have been achieving clinically effective results.
It has been known that many steps in the M phase progression are controlled by protein kinases which phosphorylate proteins. A PLK (polo-like kinases) family is serine-threonine kinase playing an important role in controlling the cell cycle including M phase, and this family includes four similar proteins of PLK1, PLK2, PLK3, and SAK (Nature. Review. Molecular. Cell Biology (Nat. Rev. Mol. Cell. Biol.), Vol. 5, 429, (2004)). Of these, PLK1 is known to participate in a plurality of important stages at M phase in mammalian cells: PLK1 has been reported to participate in each step of entering the M phase, control of centrosome, separation of chromosome, and cytokinesis, by phosphorylating various substrates (Nature. review. Molecular. Cell Biology.) (Nat. Rev. Mol. Cell Biol.), Vol. 5, 429, (2004)).
Moreover, there are many reports suggesting that PLK1 is overexpressed in various cancerous tissues in humans. For example, PLK1 is approved to be overexpressed in non small cell lung cancer (Oncogene, Vol. 14, 543, (1997)) and head and neck cancer (Cancer Research, Vol. 15, 2794, (1999)), and there are data showing that the overexpression of PLK1 is in relation with a prognosis of patients with those diseases. It is also reported that the expression of PLK1 is increased in other types of cancer such as in colon cancer, esophageal cancer, ovarian cancer, and melanoma. Such reports suggest that the overexpression of PLK1 is related to malignant alteration of cells in one way or another, and also that the function of PLK1 is important particularly in the progression of M phase in cancer cells.
From these facts, PLK1 is thought to be a possible target for antitumor approach. In fact, there are many reports on experiments for examining the inhibitory effect on the function of PLK1 against cancerous cells by using various experimental techniques. For example, it is reported that in the experiment of expressing a function-inhibited PLK1 mutant in cells by using a viral vector, PLK1 inhibition promotes the cancerous cell-selective apoptosis (Cell growth & Differentiation (Cell growth & Diff.), Vol. 11, 615, (2000)). There is also a report showing that PLK1 siRNA induces cancer cell growth inhibition and apoptosis (Journal of National Cancer Institute (J. Natl. Cancer Inst.), Vol. 94, 1863 (2002)). In addition, it is reported that PLK1 shRNA (Journal of National Cancer Institute (J. Natl. Cancer Inst.), Vol. 96, 862, (2004)), or an antisense oligonucleotide (Oncogene, Vol. 21, 3162 (2002)) gives an antitumor effect in a mouse xenograft model. Those experimental results show that inhibition of the PLK1 activity causes the promotion of cancer cell growth inhibition and apoptosis, and strongly suggest that a PLK1 inhibitor be an effective antitumor agent.
The present inventors have filed a patent application on a substituted imidazole derivative having a PLK inhibitory effect (International Publication WO2006/025567).